The invention provides proof in principle of the practicality for medical purposes of imaging body tissue, and in particular, neural tissue, especially the brain, using spectrophotometric techniques.
Certain prior work has produced low resolution shadowgrams of the exterior of the cortex, lacking edges or defined contours.
We have shown that by employing an array of ports for a set of single source, single detector pairs, and by implementing the system to acquire a sequence of data sets, distinct difference image data sets can be realized that are useful in diagnosis and treatment, e.g. on a real time basis, with relatively low expense. Blood volume and oxygenation, for instance, can be directly imaged.
We have demonstrated in brain models and human brains, that an optical imaging device can localize the activated area of the human brain. We have produced defined images that show that single functions of the brain such as observing an object (visual), moving a small part of the body (sensory motor) and thinking (cognition) appear to activate only an area as small as 0.5 to 1 cm of the brain cortex. The place of activation observed from the produced image was where it was expected. In the case of side-by-side source and detector pair, between which the probability pattern of photons takes a banana shape, the theoretical resolution and sensitive depth depends on the source-detector distance (half of the distance). By selection of the source-detector distance, a resolution of the image as good as 1.25 cm has been obtained. Imaging of white brain matter to selected depths is realized by increasing the spacing up to 7 cm.
By acquiring the images quickly (2 to 8 seconds for a data set, within about 20 seconds for a distinct difference image data set) we have demonstrated the practicability of optical imaging as a tool for the fields of psychiatry, psychology, neurology, patho-physiology, surgery, etc. Direct contact of the input and output ports with the subject lead to favorable signal-to-noise ratio that leads to good image resolution. In particular, direct contact of an array of miniature sources (lamps or diodes) and detectors has provided ample signal.
By the ability to obtain images in a short span of time (within a few minutes, typically within less than a minute), the field of real-time noninvasive and nonharmful optical monitoring of tissue at a depth from the surface is shown to be within practical grasp.
Using optical techniques avoids tissue damage, can be done inexpensively, and can provide other advantages compared to MRI, FMRI, P.E.T., E.G.G. mapping and the like.
For instance, the source and detector module are readily affixed to the head or other body part, as by a helmet, and alleviate a serious problem of artifacts related to movement of the subject relative to the detector during the time of taking an image that occurs with other imaging techniques.
The work reported here leads to diagnosis of impairment due to trauma, stroke, Alzheimer""s disease, and various patho-physiological manifestations. Furthermore the invention, together with current knowledge in the field, shows practicality of the technique in wide fields of utility, encompassing the detection and imaging of local perturbation or change related broadly to mental function, physiological function and biochemical function.
It is shown that light sources that provide no safety hazard, at relatively low cost can be usefully employed in true imaging. By employing difference measurements, the uncertainties normally limiting continuous wave spectroscopy (CWS) to trend indications are avoided. The greater information content of phase modulation and time resolved spectroscopy leads to even more informative images.
According to one important aspect of the invention, an optical system is provided for in vivo, non-invasive imaging of tissue change comprising an optical module including an array of input ports and detection ports located in a selected geometrical pattern to provide a multiplicity of arrayed single source, single detector pairs engaged directly with the subject, a spectrophotometer including a light source means constructed to introduce electromagnetic radiation of visible or infra-red wavelength into the examined tissue successively at the input ports, the wavelength being sensitive to a constituent of the imaged tissue, detector means constructed to detect, at the detection ports, radiation of the selected wavelength that has migrated in the tissue from respective input ports, and a processor receiving signals of the detected radiation from the detector means, and constructed and arranged to create a defined spatial image of the tissue by effectively producing from signals from the multiplicity of arrayed single source, single detector pairs, a succession of data sets representing, from a selected view, a succession of spatial images of the tissue, and an image data set related to differences between data of the successive data sets.
In another important aspect of the invention, an optical system is provided for in vivo, non-invasive functional neuroimaging of tissue comprising a stimulator constructed to stimulate a selected functional activity of neural tissue of interest, an optical module including an array of input ports and detection ports located in a selected geometrical pattern to provide a multiplicity of arrayed single source, single detector pairs engaged directly with the subject, a spectrophotometer including light source means constructed to introduce electromagnetic radiation of visible or infra-red wavelength into the examined neural tissue successively at the input ports, the wavelength being sensitive to a tissue constituent associated with a physiological response of the imaged functional activity, detector means constructed to detect, at the detection ports, radiation of the selected wavelength that has migrated in the stimulated neural tissue from respective input ports, and a processor receiving signals of the detected radiation from the detector means, and constructed and arranged to create a defined spatial image of the functional activity of neural tissue by effectively producing from the signals from the multiplicity of arrayed single source, single detector pairs, a first data set representing, from a selected view, a spatial image of the neural tissue at rest, a second data set representing, from the same selected view, a spatial image of the neural tissue during stimulation, and a functional image data set that is related to the differences between the first and second data sets, over the sets.
Preferred embodiments of these aspects of the inventions have one or more of the following features.
The optical module is constructed to maintain a selected distance between the input and detection ports for the respective source-detector pairs during the production of the first and second data sets, the distance being selected according to the tissue depth desired to be imaged.
The optical module or an associated set of the modules is constructed to take readings at different depths to produce 3D data sets from which an image date set may be produced.
The processor is adapted to produce the image data set by implementing an optical tomography algorithm.
The optical tomography algorithm preferably employs factors related to determined probability distribution of photons attributable to the scattering character of the tissue being imaged.
The optical system is constructed to form the image data set from a part of the head. In particular embodiments the optical system is constructed to form the functional image data set from below the surface region of the cortex.
The stimulator is constructed to stimulate the visual cortex, the cognitive cortex, the sensory motor cortex, or spinal tissue.
In various embodiments the stimulator is constructed to deliver electrical signals to selected tissue, apply an electrical field to selected tissue, or deliver magnetic signals to selected tissue.
In various embodiments the image set is related to at least one of the group consisting of blood volume, hemoglobin oxygenation or deoxygenation, photon absorption coefficient, photon scattering coefficient, refractive index, change in magnetic field, change in electric field, production of or change of a specific tissue constituent, and production of or change in the concentration of a pigment.
In various embodiments the tissue constituent is an endogenous pigment, for example hemoglobin, or an exogenous pigment, for example a selected contrast agent.
The source means, the detector means, the source to detector distance, and the rate of excitation and detection are selected to enable an image data set to be obtained within a short time, i.e., within minutes, preferably within a minute or less.
In certain embodiments, the spectrophotometer further includes a first oscillator constructed to generate a first carrier waveform at a first frequency on the order of 108 Hz, the first frequency having a time characteristic compatible with the time delay of photon migration from an input port to a detection port in the examined tissue, the light sources means being coupled to the first oscillator and constructed to generate the radiation modulated by the first carrier waveform, a phase detector constructed to determine change in waveform of the detected radiation relative to the waveform of the introduced radiation and measure therefrom the phase shift of the detected radiation at the wavelength, the phase-shifted radiation being indicative of scattering or absorptive properties of the examined tissue, and the processor constructed to create the functional image data set based at least in part on the measured phase shift.
Preferably, this optical system further comprises a second oscillator constructed to generate a second waveform at a second frequency, the detector means arranged to receive a reference waveform at a reference frequency offset by a frequency on the order of 103 Hz from the first frequency and to produce a signal, at the offset frequency, corresponding to the detected radiation, and the phase detector adapted to compare, at the offset frequency, the detected radiation with the introduced radiation and to determine therefrom the phase shift at the wavelength.
In certain other embodiments the spectrophotometer includes a light source means that is constructed to generate pulses of radiation of the wavelength, the pulses having duration on the order of a nanosecond or less, the detector means being constructed to detect over time photons of modified pulses that have migrated in the tissue from the input ports, an analyzer, connected to the detector means, adapted to determine a change in the pulse waveform shape of the detected pulses relative to the introduced pulses, at the wavelength, and the processor being constructed and arranged to create the image data set based on the determined pulse waveform change.
Preferably, this processor is constructed and arranged to calculate the effective pathlength of photons of the wavelength migrating between the input and detection ports in conjunction with creating the image data set.
In certain embodiments of this aspect of the invention the processor is constructed and arranged to calculate the scattering coefficient at the wavelength in conjunction with creating the image data set.
Also, in certain embodiments, the processor is constructed and arranged to calculate the absorption coefficient at said wavelength in conjunction with creating the image data set.
In preferred embodiments the optical system is constructed to introduce and detect photons at two wavelengths selected to provide sensitivity to a property of the constituent.
In certain preferred embodiments, the source means of the optical system comprises an incandescent lamp, and preferably a set of miniature lamps directly contacting the subject.
In other preferred embodiments the source comprises a photo diode, and preferably a set of photo diodes directly contacting the subject.
According to another important aspect of the invention, an instrument is provided for functional imaging of brain activity of a subject comprising a brain imager, including an array of sources and detectors defining a multiplicity of source-detector pairs, constructed and arranged to image hemoglobin, deoxyhemoglobin or blood volume within the brain during administration of a respective stimulus to the subject, said brain imager including a processor receiving signals of the detected radiation from the detector, and constructed and arranged to create a defined spatial image of the functional activity of neural tissue by effectively producing a first data set representing, from a selected view, a spatial image of blood in the cortex while the subject is at rest, a second data set representing, from the same selected view, a spatial image of the blood in the cortex during stimulation, and a functional image data set that is related to the differences between the first and second data sets, over the sets.
Preferred embodiments of this aspect of the invention have one or more of the following features.
The device is in the form of a near infrared hemoglobinometer based on introducing and detecting photons that have migrated through tissue of the head, the device preferably having multiple source-detector pairs for engaging the skull, with the source being spaced from the detector for selected pairs between about 1.5 and 7 cm, preferably in certain instances the spacing being 2.5 cm or greater. The device has a multiplicity of light sources and detectors defining an array of source-detector pairs, and a control for energizing one source at a time enabling accumulation of single source-detector responses.
The light source or sources are incandescent lamps, LEDs, laser diodes or other lasers.
The instrument comprises an array of sources of near infrared or visible photons, an array of detectors positioned to receive photons from the sources in respective source-detector pairs following migration of the photons from the sources through the tissue, a system enabling numerous readings of migrated photons to be taken systematically at the detectors for different source-detector positions relative to the tissue, and a processor employing an imaging algorithm based on respectively different probabilities for a given source-detector position, for photons from the source passing through different regions of the volume of the scattering tissue that are located at different positions distributed laterally from a straight reference line between source and detector.
According to another important aspect of the invention, an instrument is provided for functional imaging of brain activity of a subject comprising an imager constructed and arranged to image hemoglobin, deoxyhemoglobin or blood volume, the imager comprising an array of sources of near infrared or visible photons, and array of detectors positioned to receive photons from the sources following migration of photons from the sources through the tissue, a system enabling numerous readings of migrated photons to be taken systematically for different source-detector positions relative to the tissue, and a processor employing data sets taken during rest and during stimulation, with an imaging algorithm that is based on respectively different probabilities for a given source-detector position, for photons from the source passing through different regions of the volume of the scattering tissue that are located at different positions distributed laterally from a straight reference line between source and detector.
The imaging algorithm is a back-projection algorithm, and the probabilities are implemented as respectively different weight factors employed in the algorithm for detected energy for different pixels of the image.
Instruments made according to the various main aspects of the invention may have one or more of the following features. The instrument is constructed to store at least one set of data for a given area of the brain while the subject is at rest and at least one set of data for the given area of the brain while the subject is stimulated, and to produce an output image representing the differences over the area of the respective sets of data.
The light sources produce relatively long light pulses and the instrument functions according to continuous wave spectroscopy, preferably the imaging instrument being constructed to take and employ readings at least at two different wavelengths.
An incandescent lamp is provided to produce the photons introduced at the sources, preferably an array of miniature incandescent lamps being arranged to be sequentially illuminated.
Each source is laterally displaced from its detector or detectors on the surface of a subject at a side by side spacing between about 1.5 and 7 cm to establish a banana-shaped probability gradient of migrating photons in the tissue that extends from source to detector.
The invention also features methods of producing an image from a volume of light-scattering tissue of a living subject comprising, providing and employing on the subject an imaging instrument according to any of the foregoing aspects. In certain preferred embodiments of the methods an optical contrast agent or a drug is introduced to the blood stream of the subject, and the instrument is employed to produce an image data set for the tissue while the contrast agent or drug is present in blood circulating in the tissue of the subject or is present in localized tissue.
These and other features and advantages of the invention will be understood from the drawings, the following description of preferred embodiments and the claims.